scholarly journals Transient Receptor Potential Ankyrin-1 (TRPA1) Block Protects against Loss of White Matter Function during Ischaemia in the Mouse Optic Nerve

2021 ◽  
Vol 14 (9) ◽  
pp. 909
Author(s):  
Wendy Lajoso ◽  
Grace Flower ◽  
Vincenzo Giacco ◽  
Anjuli Kaul ◽  
Circe La Mache ◽  
...  
Keyword(s):  
White Matter ◽  
Optic Nerve ◽  
Transient Receptor Potential ◽  
Neuronal Excitability ◽  
Receptor Potential ◽  
Glucose Deprivation ◽  
Compound Action Potential ◽  
Oxygen And Glucose Deprivation ◽  
Neuronal Transmission ◽  
Transient Receptor

Oligodendrocytes produce myelin, which provides insulation to axons and speeds up neuronal transmission. In ischaemic conditions, myelin is damaged, resulting in mental and physical disabilities. Recent evidence suggests that oligodendrocyte damage during ischaemia can be mediated by Transient Receptor Potential Ankyrin-1 (TRPA1), whose activation raises intracellular Ca2+ concentrations and damages compact myelin. Here, we show that TRPA1 is constitutively active in oligodendrocytes and the optic nerve, as the specific TRPA1 antagonist, A-967079, decreases basal oligodendrocyte Ca2+ concentrations and increases the size of the compound action potential (CAP). Conversely, TRPA1 agonists reduce the size of the optic nerve CAP in an A-967079-sensitive manner. These results indicate that glial TRPA1 regulates neuronal excitability in the white matter under physiological as well as pathological conditions. Importantly, we find that inhibition of TRPA1 prevents loss of CAPs during oxygen and glucose deprivation (OGD) and improves the recovery. TRPA1 block was effective when applied before, during, or after OGD, indicating that the TRPA1-mediated damage is occurring during both ischaemia and recovery, but importantly, that therapeutic intervention is possible after the ischaemic insult. These results indicate that TRPA1 has an important role in the brain, and that its block may be effective in treating many white matter diseases.

scholarly journals TRPA1 block protects against loss of white matter function during ischaemia in the mouse optic nerve

2021 ◽  
Author(s):  
Grace Flower ◽  
Vincenzo Giacco ◽  
Angela Roxas ◽  
Nicola B Hamilton-Whitaker ◽  
Andra Braban
Keyword(s):  
White Matter ◽  
Optic Nerve ◽  
Action Potential ◽  
Neuronal Excitability ◽  
Glucose Deprivation ◽  
Compound Action Potential ◽  
Oxygen And Glucose Deprivation ◽  
Loss And Damage ◽  
Compound Action Potentials ◽  
Compound Action

Oligodendrocytes produce myelin which provides insulation to axons and speeds up neuronal transmission. In ischaemic conditions myelin is damaged, resulting to mental and physical disabilities. Therefore, it is important to understand how the functionality of oligodendrocytes and myelin is affected by ischaemia. Recent evidence suggests that oligodendrocyte damage during ischaemia is mediated by TRPA1, whose activation raises intracellular Ca2+ concentrations and damages compact myelin. Here, we show that TRPA1 is tonically active in oligodendrocytes and the optic nerve, as the specific TRPA1 antagonist, A-967079, decreases basal oligodendrocyte Ca2+ concentrations and increases the size of the compound action potential. Conversely, TRPA1 agonists reduce the size of the optic nerve compound action potential, and this effect is significantly reduced by the TRPA1 antagonist. These results indicate that glial TRPA1 regulates neuronal excitability in the white matter under physiological as well as pathological conditions. Importantly, we find that inhibition of TRPA1 prevents loss of compound action potentials during oxygen and glucose deprivation (OGD) and improves the recovery. TRPA1 block was effective when applied before, during or after OGD, indicating that the damage is occurring during ischaemia, but that therapeutic intervention is possible after the ischaemic insult. These results indicate that TRPA1 has an important role in the brain, and that its block may be effective in treating oligodendrocyte loss and damage in many white matter diseases.

scholarly journals Targeted millisecond-scale activation of cells using non-invasive Sonogenetics

2020 ◽  
Author(s):  
Marc Duque ◽  
Corinne A. Lee-Kubli ◽  
Yusuf Tufail ◽  
Uri Magaram ◽  
Jose Mendoza Lopez ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Transient Receptor Potential ◽  
Neuronal Excitability ◽  
Receptor Potential ◽  
Cell Types ◽  
Mammalian Brain ◽  
Non Invasive ◽  
Transient Receptor Potential A1 ◽  
Layer V ◽  
Transient Receptor

Our understanding of the nervous system has been fundamentally advanced by light- and small molecule-sensitive proteins that can be used to modify neuronal excitability. However, optogenetics requires invasive instrumentation while chemogenetics lacks temporal control. Here, we identify a candidate channel that confers sensitivity to non-invasive ultrasound on millisecond timescales. Using a functional screen, we find that human Transient Receptor Potential A1 (hsTRPA1) increases ultrasound-evoked intracellular calcium levels and membrane potentials. Ultrasound, but not agonist, -evoked, gating of hsTRPA1, requires the N-terminal tip region, intact actin cytoskeleton, and cholesterol, implicating these features in the sonogenetic mechanism. We then use calcium imaging and electrophysiology to confirm that ultrasound-evoked responses of primary neurons are potentiated by hsTRPA1. We also show that unilateral expression of hsTRPA1 in mouse layer V motor cortical neurons leads to ultrasound-evoked contralateral limb responses to ultrasound delivered through an intact skull. Finally, ultrasound induces c-fos in hsTRPA1-expressing neurons, suggesting that our approach can be used for targeted activation of neural circuits. Together, our results demonstrate that hsTRPA1-based sonogenetics can effectively and non-invasively modulate neurons within the intact mammalian brain, a method that could be extended to other cell types across species.

scholarly journals Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity

2021 ◽  
Vol 22 (5) ◽  
pp. 2370
Author(s):  
María Ángeles Bonache ◽  
Pedro Juan Llabrés ◽  
Cristina Martín-Escura ◽  
Roberto De la Torre-Martínez ◽  
Alicia Medina-Peris ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Neuronal Excitability ◽  
Primary Cultures ◽  
Receptor Potential ◽  
High Specificity ◽  
Docking Studies ◽  
Antagonist Activity ◽  
Patch Clamp Electrophysiology ◽  
Transient Receptor ◽  
Highly Hydrophobic

Transient receptor potential cation channel subfamily M member 8 (TRPM8) is a Ca2+ non-selective ion channel implicated in a variety of pathological conditions, including cancer, inflammatory and neuropathic pain. In previous works we identified a family of chiral, highly hydrophobic β–lactam derivatives, and began to intuit a possible effect of the stereogenic centers on the antagonist activity. To investigate the influence of configuration on the TRPM8 antagonist properties, here we prepare and characterize four possible diastereoisomeric derivatives of 4-benzyl-1-[(3’-phenyl-2’-dibenzylamino)prop-1’-yl]-4-benzyloxycarbonyl-3-methyl-2-oxoazetidine. In microfluorography assays, all isomers were able to reduce the menthol-induced cell Ca2+ entry to larger or lesser extent. Potency follows the order 3R,4R,2’R > 3S,4S,2’R ≅ 3R,4R,2’S > 3S,4S,2’S, with the most potent diastereoisomer showing a half inhibitory concentration (IC50) in the low nanomolar range, confirmed by Patch-Clamp electrophysiology experiments. All four compounds display high receptor selectivity against other members of the TRP family. Furthermore, in primary cultures of rat dorsal root ganglion (DRG) neurons, the most potent diastereoisomers do not produce any alteration in neuronal excitability, indicating their high specificity for TRPM8 channels. Docking studies positioned these β-lactams at different subsites by the pore zone, suggesting a different mechanism than the known N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist.

TRPC3 mediates hyperexcitability and epileptiform activity in immature cortex and experimental cortical dysplasia

2014 ◽  
Vol 111 (6) ◽  
pp. 1227-1237 ◽  
Author(s):  
Fu-Wen Zhou ◽  
Steven N. Roper
Keyword(s):  
Transient Receptor Potential ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Epileptiform Activity ◽  
Receptor Potential ◽  
Synaptic Activity ◽  
Bath Application ◽  
Enhanced Expression ◽  
Transient Receptor ◽  
Canonical Type

Neuronal hyperexcitability plays an important role in epileptogenesis. Conditions of low extracellular calcium (Ca) or magnesium (Mg) can induce hyperexcitability and epileptiform activity with unclear mechanisms. Transient receptor potential canonical type 3 (TRPC3) channels play a pivotal role in neuronal excitability and are activated in low-Ca and/or low-Mg conditions to depolarize neurons. TRPC3 staining was highly enriched in immature, but very weak in mature, control cortex, whereas it was strong in dysplastic cortex at all ages. Depolarization and susceptibility to epileptiform activity increased with decreasing Ca and Mg. Combinations of low Ca and low Mg induced larger depolarization in pyramidal neurons and greater susceptibility to epileptiform activity in immature and dysplastic cortex than in mature and control cortex, respectively. Intracellular application of anti-TRPC3 antibody to block TRPC3 channels and bath application of the selective TRPC3 inhibitor Pyr3 greatly diminished depolarization in immature control and both immature and mature dysplastic cortex with strong TRPC3 expression. Epileptiform activity was initiated in low Ca and low Mg when synaptic activity was blocked, and Pyr3 completely suppressed this activity. In conclusion, TRPC3 primarily mediates low Ca- and low Mg-induced depolarization and epileptiform activity, and the enhanced expression of TRPC3 could make dysplastic and immature cortex more hyperexcitable and more susceptible to epileptiform activity.

scholarly journals Using the Patch-Clamp technique to shed light on ion channels structure, function and pharmacology

2014 ◽  
Author(s):  
Roberta Gualdani
Keyword(s):  
Ion Channels ◽  
Patch Clamp ◽  
Transient Receptor Potential ◽  
Neuronal Excitability ◽  
Receptor Potential ◽  
Cellular Membrane ◽  
Bk Channel ◽  
K Channel ◽  
Patch Clamp Technique ◽  
Transient Receptor

Ion channels are membrane proteins that selectively allow ions to flow down their electrochemical gradient across the cellular membrane. They localize in both plasma and intracellular membranes and regulate a variety of functions such as neuronal excitability, heartbeat, muscle contraction and hormones release. Thus, understanding the molecular mechanism of ion channels function and regulation is one of the key goals of modern Biophysics. During my PhD thesis, by combining patch-clamp measurements with site-direct mutagenesis, fluorophore labeling experiments and pharmacological assays, I explored some functional and structural properties of different ion transporters: the Na+/Ca2+ exchanger (NCX); the large conductance Ca2+-voltage activated K+ channel (BK) channel; the human Transient receptor potential, member A1 (TRPA1) channel.

scholarly journals Cocaine self-administration in mice with forebrain knock-down of trpc5 ion channels

F1000Research ◽  
2013 ◽  
Vol 2 ◽  
pp. 53 ◽  
Author(s):  
Matthew B Pomrenze ◽  
Michael V Baratta ◽  
Kristin C Rasmus ◽  
Brian A Cadle ◽  
Shinya Nakamura ◽  
...  
Keyword(s):  
Dose Response ◽  
Transient Receptor Potential ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Receptor Potential ◽  
Trpc Channels ◽  
Self Administration ◽  
Data Set ◽  
Knock Down ◽  
Transient Receptor

Canonical transient receptor potential (TRPC) channels are a family of non-selective cation channels that play a crucial role in modulating neuronal excitability due to their involvement in intracellular Ca2+ regulation and dendritic growth. TRPC5 channels a) are one of the two most prevalent TRPC channels in the adult rodent brain; b) are densely expressed in deep layer pyramidal neurons of the prefrontal cortex (PFC); and c) modulate neuronal persistent activity necessary for working memory and attention. In order to evaluate the causal role of TRPC5 in motivation/reward-related behaviors, conditional forebrain TRPC5 knock-down (trpc5-KD) mice were generated and trained to nose-poke for intravenous cocaine. Here we present a data set containing the first 6 days of saline or cocaine self-administration in wild type (WT) and trpc5-KD mice. In addition, we also present a data set showing the dose-response to cocaine after both groups had achieved similar levels of cocaine self-administration. Compared to WT mice, trpc5-KD mice exhibited an apparent increase in self-administration on the first day of cocaine testing without prior operant training. There were no apparent differences between WT and trpc5-KD mice for saline responding on the first day of training. Both groups showed similar dose-response sensitivity to cocaine after several days of achieving similar levels of cocaine intake.

scholarly journals Effect of transient receptor potential vanilloid 4 activation on the delayed rectifier potassium current in the hippocampal pyramidal neurons and Kv subunit expression in the hippocampi of mice

2020 ◽  
Author(s):  
Li Zhou ◽  
Weixing Xu ◽  
Dong An ◽  
Chen Men ◽  
Yingchun Li ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Receptor Potential ◽  
Delayed Rectifier ◽  
Transient Receptor Potential Vanilloid ◽  
Hippocampal Pyramidal Neurons ◽  
Protein Levels ◽  
Voltage Dependent ◽  
Transient Receptor

Abstract Activation of transient receptor potential vanilloid 4 (TRPV4) can increase hippocampal neuronal excitability. Recent studies have reported that TRPV4 may be involved in the pathogenesis of epilepsy. Voltage-gated potassium channels (VGPCs) play an important role in regulating neuronal excitability and abnormal VGPCs expression or function is related to epilepsy. Activation of TRPV4 can modulate ion channels, but whether activation of it could modulate VGPCs in hippocampal neurons remains unknown. Here we examined the effect of TRPV4 activation on the delayed rectifier potassium current (IK) in the hippocampal pyramidal neurons and on the Kv subunits expression. We also explored the role of TRPV4 in changes in Kv subunits expression in mice following pilocarpine-induced status epilepticus (PISE). Application of TRPV4 agonists, GSK1016790A and 5,6-EET, markedly reduced IK in the hippocampal pyramidal neurons, shifted the voltage-dependent inactivation curve to the hyperpolarization direction, and had no effect on the voltage-dependent activation curve. GSK1016790A- and 5,6-EET-induced inhibition of IK was blocked by TRPV4 specific antagonists, HC-067047 and RN1734. GSK1016790A-induced inhibition of IK was markedly attenuated by calcium/calmodulin-dependent kinase II (CaMKII) antagonist, but was not affected by protein kinase C or protein kinase A antagonists. Application of GSK1016790A for up to 1 h did not change the hippocampal protein levels of Kv1.1, Kv1.2, or Kv2.1. Intracerebroventricular injection of GSK1016790A for 3 d reduced the hippocampal protein levels of Kv1.2 and Kv2.1, leaving that of Kv1.1 unchanged. Kv1.2 and Kv2.1 protein levels were reduced markedly in hippocampi on day 3 post PISE, which was significantly reversed by HC-067047. We conclude that activation of TRPV4 inhibits IK in the hippocampal pyramidal neurons, possibly by activating CaMKII. Persistent activation of TRPV4 decreased Kv1.2 and Kv2.1 expression, which may be associated with the decrease in Kv1.2 and Kv2.1 expression following PISE.

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